© 2000 American Heart Association, Inc.
MiniReview |
Oxidant Signaling in Vascular Cell Growth, Death, and Survival
A Review of the Roles of Reactive Oxygen Species in Smooth Muscle and Endothelial Cell Mitogenic and Apoptotic Signaling
From The Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Kaikobad Irani, MD, The Johns Hopkins University School of Medicine, Ross 1023, 720 Rutland Ave, Baltimore, MD 21205. E-mail kirani{at}mail.jhmi.edu
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Abstract |
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 Top Abstract IntroductionSmooth Muscle CellsEndothelial CellsSources of ROS in...Potential Targets of ROS...The Answer to the...SummaryReferences |
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Abstract—Reactive oxygen species (ROS) have been traditionally regarded as toxic byproducts of aerobic metabolism. However, ROS can also act as intracellular signaling molecules in vascular cells. ROS can mediate phenotypes in vascular endothelial and smooth muscle cells that may be considered both physiological and pathophysiological. Among these are growth, apoptosis, and survival. The specific response elicited by reactive oxygen intermediaries is determined by their specific intracellular target(s). This, in turn, is dependent on the species of oxidant(s) produced, the source and therefore subcellular localization of the oxidant(s), the kinetics of production, and the quantities produced. A fuller understanding of how ROS regulate mitogenesis and apoptosis in vascular smooth muscle and endothelial cells will permit the development of novel strategies to modify or prevent vascular diseases in which these phenotypes predominate.
Key Words: reactive oxygen species • intracellular signaling
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Introduction |
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TopAbstractIntroductionSmooth Muscle CellsEndothelial CellsSources of ROS in...Potential Targets of ROS...The Answer to the...SummaryReferences |
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This MiniReview is part of a thematic series on Oxidant Signaling in Cardiovascular Cells, which includes the following articles: NAD(P)H Oxidase: Role in Cardiovascular Biology and Disease
Oxidant Signaling in Vascular Cell Growth, Death, and Survival
Antiatherogenic Mechanisms of Antioxidants Crosstalk Between Nitric Oxide and Lipid Oxidation Systems: Implications for Vascular Disease Oxygen Radicals and Endothelial Dysfunction Vascular Oxygen Species Generation
David G. Harrison, Guest Editor
Many cells that comprise the vasculature generate reactive oxygen species (ROS). Conventional thought has generally regarded these elementary molecules as harmful to the vasculature, leading to such pathological processes as hypertension, restenosis, and atherosclerosis. However, controlled clinical trials have failed to show a consistent benefit of antioxidants on atherosclerotic disease and its sequelae.1 2 3 Although a number of factors may contribute to this lack of efficacy, one intriguing possibility is that ROS through their many effects on vascular cells play both a physiological and pathophysiological role in vascular homeostasis. The purpose of this review is to summarize the varied effects that ROS have on vascular smooth muscle and endothelial cell growth, death, and survival. The pertinent redox-sensitive targets of ROS in these cells that mediate these effects will be discussed. Finally, a hypothesis for the mechanism(s) by which ROS result in diverse phenotypes in endothelial and smooth muscle cells will be presented.
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Smooth Muscle Cells |
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TopAbstractIntroductionSmooth Muscle CellsEndothelial CellsSources of ROS in...Potential Targets of ROS...The Answer to the...SummaryReferences |
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Vascular smooth muscle cell (SMC) accumulation and hypertrophy are characteristic of atherosclerotic, restenotic, and hypertensive vascular diseases (reviewed in Reference 4 ). The net balance between proliferation and apoptosis determines the extent of SMC growth.
Proliferation
SMCs respond to growth factor stimulation with intracellular
production of ROS. Such ligands include those acting via
tyrosine kinase receptors such as platelet-derived growth factor
(PDGF)5 and G protein–coupled receptors such as
phenylephrine6 and thrombin.7 For
instance, PDGF, a mitogen implicated in atherogenesis, stimulates the
production of H2O2
in vascular SMCs and leads to SMC growth. Suppression of the
PDGF-stimulated rise in
H2O2 blunts this
proliferative response. Similarly, thrombin stimulates
H2O2 and superoxide
production in SMCs.7 Suppression of these ROS by
treatment with catalase or superoxide dismutase inhibits
thrombin-induced mitogenesis. Finally, stimulation of SMCs with
phenylephrine leads to induction of
H2O2, suppression of which
inhibits phenylephrine-induced
proliferation.6
A role for ROS, especially H2O2, in SMC growth is further supported by the finding that exogenous H2O2 or chemical agents that generate ROS induce tyrosine phosphorylation of mitogen-activated protein kinases, and cell growth.5 8 9 10 Taken together, these studies strongly suggest that ROS, and H2O2 in particular, mediate the proliferative phenotype in vascular SMCs.
Survival
In parallel to their important role in SMC proliferation,
ROS have also been shown to be necessary for SMC survival. Suppression
of endogenous intracellular
H2O2, through
overexpression of catalase or treatment with membrane-permeable
antioxidants, not only inhibits proliferation but also promotes
apoptosis in SMCs.11 12 Thus, ROS, and
H2O2 in particular, act as
signaling intermediaries in antiapoptotic pathways in vascular
SMCs.
Hypertrophy
Angiotensin II (Ang II), a
proinflammatory mediator implicated in atherosclerosis,
restenosis, and hypertension,13 leads to the
hypertrophic response in SMCs via the production of both
superoxide and H2O2 and
activation of p38 MAPK.14 15 Suppression of ROS inhibits
Ang II–induced hypertrophy. Thus, ROS have also been
linked with Ang II–induced pathological SMC
hypertrophy.
Apoptosis and Growth Arrest
ROS, in addition to acting as growth-promoting signaling
molecules, can also suppress growth and/or lead to programmed cell
death in SMCs. Overexpression of the tumor suppressor gene p53 leads to
an increase in ROS in SMCs, growth inhibition, and/or
apoptosis.16 Furthermore, suppression of
p53-induced ROS abrogates p53-induced apoptosis. Thus, in the
context of p53-regulated cell-cycle progression, ROS are negative
regulators of vascular SMC growth and survival. The
physiological significance of these findings is
supported by studies showing that p53 is an important
endogenous regulator of SMC growth, and that inactivation
of p53 is strongly associated with pathological SMC proliferation in
human restenotic lesions.17
Other studies using exogenously generated oxidants have similarly reported that ROS lead to cell death of SMCs.18 19 Interestingly, some of these studies have shown that exposure of SMCs to relatively low levels of oxidant stress for short periods promotes growth, whereas prolonged exposure to higher concentrations leads to cell death. Moreover, the species of oxidant added was important in determining the fate of the cell: superoxide resulted in cell growth whereas H2O2 led to cell death.
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Endothelial Cells |
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Endothelial cell (EC) growth, death, and function are important determinants of vascular homeostasis.
Apoptosis
Although a causative role for EC apoptosis in the
pathogenesis of vascular diseases has not been proven, mounting
evidence shows that EC loss is a prominent feature of human
atherosclerosis.20 Apoptotic ECs
become procoagulant.21 In addition, the importance of EC
apoptosis in atherogenesis and the role of ROS in this process
are supported by studies showing that many risk factors for vascular
disease promote apoptotic death of ECs through redox-dependent
signaling. These include oxidized LDL and
lipoprotein(a),22 23 24 high glucose and
insulin,25 26 and Ang II.27 28 Moreover, ROS
have been implicated in EC anoikis.29 Thus, ROS may play
an important role in mediating apoptotic death in ECs that lose
their interaction with the subendothelial matrix as
seen at sites of atherosclerosis and those exposed to
proatherogenic factors.
Survival
Although the role of ROS in promoting
endothelial dysfunction and death has been well
studied, the role of endogenously generated ROS in EC
survival is relatively unknown. In nonvascular cells, superoxide
production regulated by the small GTPase Rac1 protects against
apoptosis.30 Similarly, recent evidence from our
laboratory also points toward a crucial role for ROS generated by a
Rac1-regulated oxidase in suppressing EC death via activation of
nuclear factor-
B, whereas ROS produced independent of Rac1 promote
EC apoptosis.31 Thus, by most accounts,
endothelial production of ROS leads to cell
death or promotes dysfunction. On the other hand, ROS specifically
produced by a Rac1-regulated oxidase appear to prevent
apoptosis of ECs.
The Table
summarizes the role of ROS in SMC and EC growth,
apoptosis, and survival.
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Sources of ROS in SMCs and ECs: The Importance of an NAD(P)H Oxidase |
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The observation that SMCs and ECs are capable of producing ROS has spurred a great deal of interest in identifying the enzymatic source(s) of these oxidants. A variety of cellular enzymes are potential candidates, including those involved in arachidonic acid metabolism, microsomal cytochrome P-450, xanthine oxidase, and mitochondrial electron transport. Arguably the most exciting recent discovery in this area is that ECs and SMCs possess an NAD(P)H oxidase activity analogous to the multicomponent phagocyte NADPH oxidase. The functional characteristics of this oxidase and its importance in cardiovascular biology and disease are covered in much greater detail in another review in this thematic series.32 Suffice it to say that many, although not all, components of this oxidase have been identified at the RNA or protein levels in SMCs and ECs.7 33 34 35 36 37 In addition, Rac1, a small GTPase that is an essential regulatory component of the phagocyte oxidase,38 is ubiquitously expressed.
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Potential Targets of ROS in ECs and SMCs |
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TopAbstractIntroductionSmooth Muscle CellsEndothelial CellsSources of ROS in...Potential Targets of ROS...The Answer to the...SummaryReferences |
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The list of intracellular targets of ROS is growing rapidly. A detailed review of this list is beyond the scope of this article. However, within the context of vascular cell growth and apoptosis, certain names merit particular attention (Figure
).
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Extracellular Signal–Regulated Kinases
The mitogen-activated protein kinase (MAPK) family,
also known as extracellular signal–regulated kinases (ERKs), is
activated by exogenous
H2O2 and by
endogenously generated ROS in SMCs stimulated with growth
factors.5 ERKs are important mediators of proliferation.
Activation of ERKs has also been implicated in vascular
endothelial growth factor (VEGF)–induced EC
survival.39
Stress-Activated Protein Kinases
Kinases belonging to the stress-activated protein
kinase (SAPK) family, which include c-Jun N-terminal kinases (JNKs) and
p38 MAPK, are also sensitive to redox modulation (reviewed in Reference
40 ). Members of the Rho family of small GTPases
including Rac1 regulate these kinases.40 In contrast to
ERKs, JNKs and their downstream target c-Jun, have been implicated in
H2O2 and other
stress-induced apoptosis of ECs.41 42 Moreover,
p38 MAPK has been implicated in EC upregulation of intercellular
adhesion molecule-1 and, therefore, endothelial
dysfunction.43 In SMCs, redox-sensitive activation of p38
MAPK mediates Ang II–induced hypertrophy14
and has also been implicated in SMC migration.44
Nuclear Factor-B (NF-B)
Activation of the transcription factor NF-B has been
associated with EC dysfunction and vascular
inflammation.45 NF-B–mediated transcription is also
important in cell survival (reviewed in Reference 46 ).
The activation of NF-B by ROS, specifically ROS generated by a
Rac1-regulated NAD(P)H oxidase, has been shown in HeLa
cells.47 In SMCs, constitutive activation of NF-B has
been reported to be essential for proliferation.48 In
addition, Ang II–induced effects on SMCs may also be mediated via
NF-B.49 In ECs, NF-B is a prime target for ROS, and
its activation has been linked to EC dysfunction (reviewed in Reference
45 ) and survival.31 50 51 52 53
Akt Kinase
Akt is a kinase, which lies downstream of
phosphoinositide 3-kinase (PI 3-kinase), and is
involved in antiapoptotic signaling (reviewed in Reference
54 ). It is regulated by ROS in Ang II–stimulated
SMCs.55 In ECs, activation of Akt has been linked to the
protective effects of shear stress56 and VEGF-induced
growth and survival.57 58 59 Rac1 is a target for the
products of PI 3-kinase,60 implicating a
Rac1-regulated, NAD(P)H-dependent oxidase in the signaling pathways
involving Akt in ECs and SMCs.
Caspases
Caspases are cysteine proteases that execute the
apoptotic message. Caspases are sensitive to redox changes in
the cell (reviewed in Reference 61 ). Specifically, in
ECs, processing and activity of the downstream caspase-3 in response to
cell detachment29 or tumor necrosis factor (TNF)
stimulation31 are regulated by ROS.
It is worth emphasizing that many of the signaling proteins mentioned above that are sensitive to the redox state of the cell may not be direct targets of ROS. In fact, it is very likely that one or more intermediary proteins are involved. Tyrosine phosphatases are prime candidates for such intermediaries. Such phosphatases all have redox-sensitive cysteine residues in their active sites,62 which are essential for their biological activity.63 The generally accepted paradigm is that an increase in intracellular ROS by inhibiting tyrosine phosphatase activity transiently tips the balance toward tyrosine kinases that then leads to phosphorylation of their cellular targets, such as ERKs and SAPKs.
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The Answer to the Paradox: What, Where, How, and How Much? |
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TopAbstractIntroductionSmooth Muscle CellsEndothelial CellsSources of ROS in...Potential Targets of ROS...The Answer to the...SummaryReferences |
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The studies reviewed above show that ROS generated within vascular SMCs and ECs can either induce cell growth or arrest or promote survival or death, thereby leading to vascular dysfunction or acting as mediators of physiological vascular function. Although recently appreciated in vascular biology, such apparently paradoxical roles of ROS have been recognized in other fields of biology. The explanation to this paradox has been hinted at in the studies reviewed above and is probably a combination of the following factors:
- What: The Species of Oxidant(s) Produced and the Proportion
of Different Oxidant Species. Certain highly reactive oxidant species
such as ·OH and peroxynitrite are more
cytotoxic than others (reviewed in Reference 64 ).
Moreover, ROS have differential effects on cellular targets such as
ERKs10 and on cell growth.18 Thus, the redox
milieu of the cell including its iron content and expression of
antioxidant enzymes such as superoxide dismutase, glutathione
peroxidase, and catalase, which play an important part in determining
the species and amounts of ROS, is probably a key factor in determining
the response of a cell to ROS production.
- Where: The Subcellular Localization of the ROS. Similar
to nitric oxide synthases, oxidoreductases are spatially distributed in
a selective fashion,65 effectively controlling access of
targets for ROS produced from different intracellular sources.
- How: The Kinetics of ROS Production. The kinetics
of oxidant production could differentially activate
and/or inhibit targets such as transcription factors, resulting in a
host of cellular responses. Such differential activation of
transcription factors allows the cell to use the same second messenger
to elicit varied responses and is known to exist for other well-known
second messengers systems such as
Ca2+.66
- How Much: The Amplitude of ROS Production. The
quantities of ROS produced probably have a profound effect in
determining the fate of the cell. This is supported by observations
that activation of specific redox-sensitive kinases such as ERKs and
p38 MAPK in SMCs is very dependent on the concentration of
ROS.5 14
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Summary |
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TopAbstractIntroductionSmooth Muscle CellsEndothelial CellsSources of ROS in...Potential Targets of ROS...The Answer to the...SummaryReferences |
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The experimental data to date suggest potential conflicting roles of oxidants in the genesis of vascular disorders. This presents a challenge to scientists and clinicians alike. It is imperative that future efforts be directed toward better defining and characterizing the signaling pathways regulated by ROS in vascular cells. Such efforts will likely yield new molecular targets and ultimately more effective therapies for preventing or ameliorating vascular diseases such as atherosclerosis, restenosis, and hypertension, through fine modulation of ROS-regulated signaling.
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Acknowledgments |
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This review was supported by The Johns Hopkins University Clinician Scientist Award, The W.W. Smith Charitable Trust, the Mid-Atlantic American Heart Association, the Bernard Foundation, and the Abraham and Virginia Weiss Endowment. I thank C.J. Lowenstein for constructive criticism of this manuscript. I also thank my collaborators P.J. Goldschmidt-Clermont and T. Finkel and all the members of my laboratory for helpful comments and discussions.
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Footnotes |
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This manuscript was sent to Donald D. Heistad, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received March 10, 2000; accepted June 19, 2000.
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S. Saito, G. D. Frank, M. Mifune, M. Ohba, H. Utsunomiya, E. D. Motley, T. Inagami, and S. Eguchi Ligand-independent trans-Activation of the Platelet-derived Growth Factor Receptor by Reactive Oxygen Species Requires Protein Kinase C-delta and c-Src J. Biol. Chem., November 15, 2002; 277(47): 44695 - 44700. [Abstract] [Full Text] [PDF]
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 U. G. B. Haider, D. Sorescu, K. K. Griendling, A. M. Vollmar, and V. M. Dirsch Resveratrol Suppresses Angiotensin II-Induced Akt/Protein Kinase B and p70 S6 Kinase Phosphorylation and Subsequent Hypertrophy in Rat Aortic Smooth Muscle Cells Mol. Pharmacol., October 1, 2002; 62(4): 772 - 777. [Abstract] [Full Text] [PDF]
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Q. Hu, Z.-X. Yu, V. J. Ferrans, K. Takeda, K. Irani, and R. C. Ziegelstein Critical Role of NADPH Oxidase-derived Reactive Oxygen Species in Generating Ca2+ Oscillations in Human Aortic Endothelial Cells Stimulated by Histamine J. Biol. Chem., August 30, 2002; 277(36): 32546 - 32551. [Abstract] [Full Text] [PDF]
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W. Martinet, M. W.M. Knaapen, G. R.Y. De Meyer, A. G. Herman, and M. M. Kockx Elevated Levels of Oxidative DNA Damage and DNA Repair Enzymes in Human Atherosclerotic Plaques Circulation, August 20, 2002; 106(8): 927 - 932. [Abstract] [Full Text] [PDF]
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Y. Shizukuda and P. M. Buttrick Oxygen free radicals and heart failure: new insight into an old question Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L237 - L238. [Full Text] [PDF]
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G. NICKENIG, S. BAUDLER, C. MULLER, C. WERNER, N. WERNER, H. WELZEL, K. STREHLOW, and M. BOHM Redox-sensitive vascular smooth muscle cell proliferation is mediated by GKLF and Id3 in vitro and in vivo FASEB J, July 1, 2002; 16(9): 1077 - 1086. [Abstract] [Full Text] [PDF]
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 J. R. Sowers Hypertension, Angiotensin II, and Oxidative Stress N. Engl. J. Med., June 20, 2002; 346(25): 1999 - 2001. [Full Text] [PDF]
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C. Mueller, S. Baudler, H. Welzel, M. Bohm, and G. Nickenig Identification of a Novel Redox-Sensitive Gene, Id3, Which Mediates Angiotensin II-Induced Cell Growth Circulation, May 21, 2002; 105(20): 2423 - 2428. [Abstract] [Full Text] [PDF]
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M. Potente, U. R. Michaelis, B. Fisslthaler, R. Busse, and I. Fleming Cytochrome P450 2C9-induced Endothelial Cell Proliferation Involves Induction of Mitogen-activated Protein (MAP) Kinase Phosphatase-1, Inhibition of the c-Jun N-terminal Kinase, and Up-regulation of Cyclin D1 J. Biol. Chem., May 3, 2002; 277(18): 15671 - 15676. [Abstract] [Full Text] [PDF]
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C. Kumaran and K. Shivakumar Calcium- and superoxide anion-mediated mitogenic action of substance P on cardiac fibroblasts Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1855 - H1862. [Abstract] [Full Text] [PDF]
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M. Katsuyama, C. Fan, and C. Yabe-Nishimura NADPH Oxidase Is Involved in Prostaglandin F2alpha -induced Hypertrophy of Vascular Smooth Muscle Cells. INDUCTION OF NOX1 BY PGF2alpha J. Biol. Chem., April 12, 2002; 277(16): 13438 - 13442. [Abstract] [Full Text] [PDF]
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C. Li and R. M. Jackson Reactive species mechanisms of cellular hypoxia-reoxygenation injury Am J Physiol Cell Physiol, February 1, 2002; 282(2): C227 - C241. [Abstract] [Full Text] [PDF]
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H. P. Souza, X. Liu, A. Samouilov, P. Kuppusamy, F. R. M. Laurindo, and J. L. Zweier Quantitation of superoxide generation and substrate utilization by vascular NAD(P)H oxidase Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H466 - H474. [Abstract] [Full Text] [PDF]
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F. TOSETTI, N. FERRARI, S. DE FLORA, and A. ALBINI Angioprevention': angiogenesis is a common and key target for cancer chemopreventive agents FASEB J, January 1, 2002; 16(1): 2 - 14. [Abstract] [Full Text] [PDF]
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X.-m. Liu, G. B. Chapman, H. Wang, and W. Durante Adenovirus-Mediated Heme Oxygenase-1 Gene Expression Stimulates Apoptosis in Vascular Smooth Muscle Cells Circulation, January 1, 2002; 105(1): 79 - 84. [Abstract] [Full Text] [PDF]
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C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]
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G. Zalba, G. S. Jose, M. U. Moreno, M. A. Fortuno, A. Fortuno, F. J. Beaumont, and J. Diez Oxidative Stress in Arterial Hypertension: Role of NAD(P)H Oxidase Hypertension, December 1, 2001; 38(6): 1395 - 1399. [Abstract] [Full Text] [PDF]
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L. Rossig, J. Hoffmann, B. Hugel, Z. Mallat, A. Haase, J.-M. Freyssinet, A. Tedgui, A. Aicher, A. M. Zeiher, and S. Dimmeler Vitamin C Inhibits Endothelial Cell Apoptosis in Congestive Heart Failure Circulation, October 30, 2001; 104(18): 2182 - 2187. [Abstract] [Full Text] [PDF]
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D. R. S. Steiner, N. C. Gonzalez, and J. G. Wood Leukotriene B4 promotes reactive oxidant generation and leukocyte adherence during acute hypoxia J Appl Physiol, September 1, 2001; 91(3): 1160 - 1167. [Abstract] [Full Text] [PDF]
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M. V. Gurjar, J. DeLeon, R. V. Sharma, and R. C. Bhalla Mechanism of inhibition of matrix metalloproteinase-9 induction by NO in vascular smooth muscle cells J Appl Physiol, September 1, 2001; 91(3): 1380 - 1386. [Abstract] [Full Text] [PDF]
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S. L. Lee, A. R. Simon, W. W. Wang, and B. L. Fanburg H2O2 signals 5-HT-induced ERK MAP kinase activation and mitogenesis of smooth muscle cells Am J Physiol Lung Cell Mol Physiol, September 1, 2001; 281(3): L646 - L652. [Abstract] [Full Text] [PDF]
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 T.-H. Hung, J. N. Skepper, and G. J. Burton In Vitro Ischemia-Reperfusion Injury in Term Human Placenta as a Model for Oxidative Stress in Pathological Pregnancies Am. J. Pathol., September 1, 2001; 159(3): 1031 - 1043. [Abstract] [Full Text] [PDF]
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H. D. Intengan and E. L. Schiffrin Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis Hypertension, September 1, 2001; 38(3): 581 - 587. [Abstract] [Full Text] [PDF]
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 A. D. Schecter, A. B. Berman, L. Yi, A. Mosoian, C. M. McManus, J. W. Berman, M. E. Klotman, and M. B. Taubman HIV envelope gp120 activates human arterial smooth muscle cells PNAS, August 10, 2001; (2001) 181328798. [Abstract] [Full Text] [PDF]
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 G. Lesage, S. Glaser, Y. Ueno, D. Alvaro, L. Baiocchi, N. Kanno, J. L. Phinizy, H. Francis, and G. Alpini Regression of cholangiocyte proliferation after cessation of ANIT feeding is coupled with increased apoptosis Am J Physiol Gastrointest Liver Physiol, July 1, 2001; 281(1): G182 - G190. [Abstract] [Full Text] [PDF]
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 W. Liu, Y. Liu, and W. L. Lowe Jr. The Role of Phosphatidylinositol 3-Kinase and the Mitogen-Activated Protein Kinases in Insulin-Like Growth Factor-I-Mediated Effects in Vascular Endothelial Cells Endocrinology, May 1, 2001; 142(5): 1710 - 1719. [Abstract] [Full Text]
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Z. Chen, K. W. Woodburn, C. Shi, D. C. Adelman, C. Rogers, and D. I. Simon Photodynamic Therapy With Motexafin Lutetium Induces Redox-Sensitive Apoptosis of Vascular Cells Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 759 - 764. [Abstract] [Full Text] [PDF]
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 M.-S. Zhou, A. Adam, and L. Raij Review: Interaction among angiotensin II, nitric oxide and oxidative stress Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S59 - S63. [PDF]
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F. C. Luft Workshop: Mechanisms and Cardiovascular Damage in Hypertension Hypertension, February 1, 2001; 37(2): 594 - 598. [Abstract] [Full Text] [PDF]
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A. D. Schecter, A. B. Berman, L. Yi, A. Mosoian, C. M. McManus, J. W. Berman, M. E. Klotman, and M. B. Taubman HIV envelope gp120 activates human arterial smooth muscle cells PNAS, August 28, 2001; 98(18): 10142 - 10147. [Abstract] [Full Text] [PDF]
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R. A. Forbes, C. Steenbergen, and E. Murphy Diazoxide-Induced Cardioprotection Requires Signaling Through a Redox-Sensitive Mechanism Circ. Res., April 27, 2001; 88(8): 802 - 809. [Abstract] [Full Text] [PDF]
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G. Cuda, R. Paterno, R. Ceravolo, M. Candigliota, N. Perrotti, F. Perticone, M. C. Faniello, F. Schepis, A. Ruocco, E. Mele, et al. Protection of Human Endothelial Cells From Oxidative Stress: Role of Ras-ERK1/2 Signaling Circulation, February 26, 2002; 105(8): 968 - 974. [Abstract] [Full Text] [PDF]
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